An emerging paradigm suggests that malignant cells exist in a complex cellular and extracellular microenvironment that significantly influences the initiation and maintenance of the malignant phenotype.1,2 Solid tumors can be seen to be composed of the malignant cell as well as the supporting cells that comprise the stroma including fibroblasts, endothelium, pericytes, lymphatics and generally, a mononuclear infiltrate.2-6 These stromal cells are so vital to the survival of the tumor that they have become an important target for chemotherapeutic intervention.
Mesenchymal stem cells (MSCs) are pluripotent progenitor cells that contribute to the maintenance and regeneration of diverse tissues7,8. MSCs can be found in many tissues where they serve as local sources of stem cells, such as bone marrow, blood or different sources of mesenchymal tissue. MSCs contribute to tissue remodelling after injury or during chronic inflammation. The damaged tissue is thought to release specific endocrins that then lead to the mobilization of multi-potent MSCs and their subsequent recruitment to the site of injury. MSCs are also strongly attracted to tumor stroma. MSCs infused into the blood in experimental animals localize to malignancies. Once there, MSCs may contribute to diverse cell types that comprise tumor stroma including tumor vasculature and stromal fibroblasts
In breast cancer, Karnoub et al. recently showed that MSCs at the tumor site release a small protein, the chemokine CCL5. CCL5 can act as a chemoattractant for diverse stromal cells9,10 and its expression is associated with increased tumour neovascularization. In addition, CCL5 may contribute to cancer growth and metastasis through the recruitment of a number of stromal cell types to sites of primary tumor growth.9,11,12 
It has recently been shown that the CD34− subpopulation of MSC progenitors undergo recruitment to the growing tumor and contribute to tumor neoangiogenesis through their differentiation into new vascular endothelial cells (ECs) or pericytes.13-15 Importantly, these and related direct effects can be observed following the direct injection of MSCs into the peripheral circulation.16 
There exists an unmet need for stem cell-based therapies that employ cytotoxic protein expression based on proximity with tumor stromal tissue per se for cytotoxic protein expression, rather than cytotoxic protein expression based on proximity with tumor tissue undergoing angiogenesis. This need is particularly acute regarding treatment of metastatic tumors that have not yet undergone angiogenesis.